Process and intermediates for the preparation of spiro(isoquinoline-4(1H), 3&#39;-pyrrolidine)-1,2&#39;, 3,5&#39;(2H)-tetrones which are useful as aldose reductase inhibitors

ABSTRACT

The invention relates to a process for producing spiro-isoquinoline pyrrolidines. The compounds have pharmaceutical properties which render them beneficial for the prevention or treatment of diabetes mellitus associated complications.

BACKGROUND OF THE INVENTION

This invention discloses an improved process and for chemical intermediates useful for the synthesis of the spiro[isoquinoline-4(1H),3'-pyrrolidine]-1,2',3,5'(2H)-tetrones represented by formula I: ##STR1## wherein: R¹ is hydrogen, halogen and R² is dihalogen substituted benzyl or methyl.

PRIOR ART

U.S. Pat. No. 4,927,831, May 22, 1990 discloses the spiro[isoquinoline-4(1H),3'-pyrrolidine]-1,2',3,5'(2H)-tetrones of formula I and their use as aldose reductase inhibitors.

SUMMARY OF THE INVENTION

The process of the present invention is illustrated by the following process: ##STR2## wherein R¹ and R² are as defined above.

The present invention includes the compound of formula (V) ##STR3## wherein R¹ and R² are as defined above.

(V) is useful as an intermediate for preparing spiro[isoquinoline]-4(1H),3'-pyrrolidine]-1,2',3,5'(2H)-tetrones of formula (I) which have strong aldose reductase inhibiting activity and are expected useful as remedies for diabetic complications.

The following examples further illustrate this invention.

EXAMPLE 1 2-[(4-Bromo-2-fluorophenyl)methyl]-6-fluorospiro[isoquinoline-4(1H),3'-pyrrolidine]-1,2',3,5'(2H)-tetrone Step a) (2-Carboxy-6-fluorophenyl)propanedioic Acid Dimethyl Ester

To a rapidly stirred cold suspension (0° C.) of 2-chloro-4-fluorobenzoic acid (20.0 g, 114.6 mmol), cuprous bromide (1.64 g, 11.46 mmol) and dimethyl malonate (250 g) was added NaH (80% in mineral oil, 8.25 g, 275.04 mmol) over a 30 minute period, while a stream of dry N₂ was passed over the mixture. After the addition of the NaH had been completed, the mixture wa stirred at 85° C. for 3 hours. At this point, the suspension had turned to a solid mass, which was dissolved in H₂ O (1000 mL). The aqueous layer was extracted with diethyl ether (3×500 mL) and was acidified with HCl (2N). The mixture was extracted with EtOAc and dried over MgSO₄. Evaporation gave an off-white solid which was recrystallized from ether/hexane (after cooling to -20° C.) to give a white solid (27.5 g, 89%). ¹ H NMR (DMSO-d₆, 400 MHz): δ 3.68 [s, 6H, (--CO₂ Me)2], 5.79 (s, 1H, Ar-H), 7.12 (dd, J=10.06 Hz, 2.61 Hz, 1H, Ar-H), 7.33 (dt, J=8.48 Hz, 2.64 Hz, 1H, Ar-H), 8.03 (dd, 8.77 Hz, 6.17 Hz, 1H, Ar-H); IR (KBr, cm⁻¹): 3400-2700 (CO₂ H), 1730 (CO), 1680 (CO); MS (m/e): 270 (M⁺)--CH₃ OH), 210 (M⁺ --CH₃ OH, --CO), 151 (M⁺ --CH₃ OH--CO--CO₂ CH₃); M.P. 121.5°-123.0° C.

Anal. Calc'd: C, 53.34; H, 4.10. Found: C, 53.36; H, 3.93.

The following compounds were prepared in substantially the same manner as that of Example 1 Step a):

(2-Carboxyphenyl)propanedioic Acid Dimethyl Ester

¹ H NMR (DMSO-d₆, 400 MHz): δ 3.67 [s, 6H, --CH(C)₂ CH₃)₂ ], 5.72 [s, 1H, --CH(CO₂ CH₃)₂, 7.3 (d, J=7.76 Hz, 1H, Ar-H), 7.45 (dt, J=7.66 Hz, 1.12 Hz, 1H, Ar-H), 7.6 (dt, J=7.66 Hz, 1.45 Hz, 1H, Ar-H), 7.94 (dd, J=7.8 Hz, 1.33 Hz, 1H, Ar-H), 13.2 (s, 1H, --CO₂ H); IR (KBr, cm⁻¹): 3300-2700 (CO₂ H), 1750 (CO), 1730 (CO), 1680 (CO); MS (m/e): 252 (M⁺), 220 (M⁺ --CH₃ OH), 188 (M⁺ --2×CH₃ OH); M.P. 119°-120° C.

Anal. Calc'd: C, 57.14; H, 4.80 Found: C, 57.05; H, 4.78

(2-Carboxy-6-chlorophenyl)propanedioic Acid Dimethyl Ester

¹ H NMR (DMSO-d₆, 200 MHz): δ 3.69 [s, 6H, (--CO₂ Me)₂ ], 5.78 [s, 1H, Ar-CH(CO₂ Me)₂ ], 7.38 (d, J=1.8 Hz, 1H, Ar-H), 7.58 (dd, J=7.8 Hz, 1.8 Hz, 1H, Ar-H), 7.96 (d, J=8.2 Hz, 1H, Ar-H), 13.5 (br s, 1H, --CO₂ H); IR (KBr, cm⁻¹): 3200-2700 (CO₂ H), 1760 (CO), 1740 (CO), 1690 (CO); MS (m/e): 286 (20 M⁺), 254 (64, M⁺ --CH₃ OH), 222 (60, M⁺ 2×CH₃ OH)

Anal. Calc'd: C, 50.28; H, 3.87. Found: C, 50.40; H, 3.87.

Step b) 2-[(4-Bromo-2-fluorophenyl)methyl]-6-fluoro-1,2,3,4-tetrahydro-1,3-dioxo-4-isoquinolinecarboxylic Acid Methyl Ester

A mixture of (2-carboxy-6-fluorophenyl)propanedioic acid dimethyl ester (6.0 g, 22.22 mmol) and SOCl₂ (50 mL) was refluxed for 1 hour. The volatiles were removed in vacuo and the acid chloride was ddissolved in THF (20 mL). In a second flask were placed 4-bromo-2-fluorobenzylamine (4.98 g, 24.44 mmol), triethylamine (15.48 mL, 111.1 mmol) and THF (150 mL). The contents of the first flask were added to the second flask and the mixture was stirred for 20 minutes. The formed suspension was poured into H₂ O (1500 mL), stirred for 10 minutes and acidified with HCl (2N). The mixture was extracted with EtOAc and the organic layer was dried over MgSO₄. Evaporation gave a yellowish solid which was recrystallized from acetone/ether/hexane (after cooling -20° C.) to give a white solid (7.85 g, 83%). ¹ H NMR (DMSO-d₆, 400 MHz): δ 3.98 (s, 3H, --CO₂ CH₃), 5.27 (s, 2H, --NCH₂ --), 7.08 (t, J=7.95 Hz, 2H, Ar-H), 7.2 (m, 1H, Ar-H), 7.34 (m, 2H, Ar-H, --OH), 7.54 (m, 1H, Ar-H), 8.1-8.26 (m, 2H, Ar-H); IR (KBr, cm⁻¹): 1680 (CO), 1660 (CO), 1610 (CO); MS (m/e): 423 (M⁺), 391 (M⁺ --CH₃ OH); M.P. 157°-158° C.

Anal. Calc'd: C, 50.97; H, 2.85; N, 3.30. Found: C, 50.86; H, 2.86; N, 3.33.

The following compounds were prepared in substantially the same manner as that of Example 1 Step b):

2-[(4-Bromo-2-fluorophenyl)methyl]-1,2,3,4-tetrahydro-1,3-dioxo-4-isoquinolinecarboxylic Acid Methyl Ester

¹ H NMR (DMSO-d₆, 400 MHz): δ [3.67, 3.99 (s, 3H, --CO₂ CH₃, tautomeric], [5.06 (q, J=15.4 Hz), 5.29 (s) 2H, N--CH₂ --, tautomeric], 5.03 (s, 1H, --CHCO₂ CH₃, tautomeric), 7.07-8.44 (m, 7H, Ar-H, tautomeric); IR (KBr, cm⁻¹): 1675 (CO), 1610 (CO), 1490 795 (m); MS (m/e): 405 (M⁺), 373 (M⁺ --MeOH); M.P. 149°-150° C.

Anal. Calc'd: C, 53.22; H, 3.23; N, 3.45. Found: C, 52.91; H, 3.20; N, 3.27. 6-Chloro-1,2,3,4-tetrahydro-2-methyl-1,3-dioxo-4-isoquinolinecarboxylic Acid Methyl Ester

¹ H NMR (DMSO-d₆, 200 MHz): δ [3.23 (s), 3.44 (s), tautomeric, 3H, -NCH₃ ], [3.71 (s), 4.03 (s), tautomeric, 3H, --CO₂ CH₃ ], 7.3-8.4 (tautomeric, Ar-H, --OH, 4H); IR (KBr, cm⁻¹): 3440 (OH), 1680 (CO), 1600 (CO); MS (m/e): 267 (M⁺), 235 (M⁺ --OMe); M.P. 166°-167° C.

Anal. Calc'd: C, 53.85; H, 3.77; N, 5.23. Found: C, 53.66; H, 3.63; N, 5.14.

1,2,3,4-Tetrahydro-2-methyl-1,3-dioxo-4-isoquinolinecarboxylic Acid Methyl Ester

¹ H NMR (DMSO-d₆, 200 MHz): δ [3.24 (s), 3.46 (s), tautomeric, 3H, -NCH₃ ], [3.7 (s), 4.03 (s), tautomeric, 3H, --CO₂ CH₃ ], 7.4-8.45 (tautomeric, 4H, Ar-H); IR (KBr, cm⁻¹): 3400 (OH), 1670 (CO), 1600 (CO); MS (m/e): 233 (M⁺), 118 (M⁺ --CO₂ Me, --CONCH₃); M.P. 130°-131° C.

Anal. Calc'd: C, 61.80; H, 4.75; N, 6.01. Found: C, 61.62; H, 4.89; N, 5.92.

Step c). 2-[(4-Bromo-2-fluorophenyl)methyl]-4-cyanomethyl-6-fluoro-1,2,3,4-tetrahydro-1,3-dioxo-4-isoquinolinecarboxylic Acid Methyl Ester

To a cold (0° C.) suspension of 2-[(4-bromo-2-fluorophenyl)methyl]-6-fluoro-1,2,3,4-tetrahydro-1,3-dioxo-4-isoquinolinecarboxylic acid methyl ester (11.0 g, 25.94 mmol), K₂ CO₃ (3.58 g, 25.94 mmol), DMF (50 mL) and acetone (50 mL) was added freshly distilled BrCh₂ CN (3.61 mL, 51.88 mmol) and the mixture was stirred for 10 hours at 0° C. and kept in the refrigerator for 4 days. The mixture was then poured into H₂ O, acidified with HCl (2N), and extracted with EtOAc. The organic extracts were dried over MgSO₄. Evaporation and purification by flash chromatography hexane/EtOAc (5/1) gave a light yellow solid (11.45 g, 95.4%). ¹ H NMR (DMSO-d₆, 300 MHz): δ 3.63 (s, 3H, --CO₂ CH₃), 3.73 (d, J=16.8 Hz, 1H, --HCHCN), 3.9 (d, J= 16.8 Hz, 1H, --HCHCN), 5.14 (dd, J=15.2 Hz, 2H, --NCH₂ --), 7.16 (t, J=8.1 Hz, 1H, Ar-H), 7.36 (dd, J=8.1 Hz, 1.8 Hz, 1H, Ar-H), 7.57 (m, 2H, Ar-H), 7.64 (dd, J=9.3 Hz, 2.4 Hz, 1H, Ar-H), 8.3 (dd, J=8.7 Hz, 5.7 Hz, 1H, Ar-H); IR (KBr, cm⁻¹): 2250 (CN), 1760 (CO), 1720 (CO), 1675 (CO); MS (m/e): 463 (M+H)⁺ ; M.P. 127°-128° C.

Anal. Calc'd: C, 51.86; H, 2.83; N, 6.05. Found: C, 51.73; H, 3.00; N, 5.96.

The following compounds were prepared in substantially the same manner as that of Example 2, Step c).

2-[(4-Bromo-2-fluorophenyl)methyl]-4-cyanomethyl-1,2,3,4-tetrahydro-1,3-dioxo-4-isoquinolinecarboxylic Acid Methyl Ester

¹ H NMR (DMSO-d₆, 400 MHz): δ 3.61 (s, 3H, --CO₂ CH₃), 3.72 (d, J=17.0 Hz, 1H, --HCHCN), 3.88 (d, J=17.0 Hz, 1H, --HCHCN), 5.14 (dd, J=15.2 Hz, 2H, --NCH₂ --), 7.17 (t,J=8.3 Hz, 1H, Ar-H), 7.39 (dd, J=8.3 Hz, 1.87 Hz, 1H, Ar-H), 7.55 (dd, J=9.7 Hz, 2.1 Hz, 1H, Ar-H), 7.68 (m, 2H, Ar-H), 7.86 (dt, J=7.7 Hz, 1.45 Hz, 1H, Ar-H), 8.21 (dd, J=7.64 Hz, 1.25 Hz, 1H, Ar-H); IR (KBr, cm⁻¹): 2240 (CN), 1760 (CO), 1720 (CO), 1680 (CO); MS (m/e): 444 (M⁺), 404 (M⁺ --CH₂ CN); M.P. 108°-110° C.

Anal. Calc'd: C, 53.94; H, 3.15; N, 6.29. Found: C, 53.94; H, 3.38; N, 5.93.

4-Cyanomethyl-2-methyl-1,2,3,4-tetrahydro-1,3-dioxo-4-isoquinolinecarboxylic Acid Methyl Ester

¹ H NMR (DMSO-d₆, 400 MHz): δ 3.31 (s, 3H, --NCH₃), 3.65 (s, 3H, --CO₂ CH₃), 3.67 (d, J=17.0 Hz, 1H, --HCHCN), 3.76 (d, J=17.0 Hz, 1H, --HCHCN), 7.58 (dd, J=7.9 Hz, 1.04 Hz, 1H, Ar-H), 7.69 (dt, J=7.9 Hz, 1.04 Hz, 1H, Ar-H), 7.84 (dt, J=7.26 Hz, 1.45 Hz, 1H, Ar-H), 8.2 (dd, J=7.3 Hz, 1.45 Hz, 1H, Ar-H); IR (KBr, cm⁻¹): 2250 (CN), 1760 (CO), 1730 (CO), 1670 (CO); MS (m/e): 272 (M⁺), 213 (M⁺ --CO₂ CH₃); M.P. 120°-122° C.

Anal. Calc'd: C, 61.76; H, 4.44; N, 10.29. Found: C, 61.72; H, 4.57; N, 10.07. 6-Chloro-4-cyanomethyl-2-methyl-1,2,3,4-tetrahydro-1,3-dioxo-4-isoquinolinecarboxylic Acid Methyl Ester

¹ H NMR (DMSO-d₆, 400 MHz): δ 3.3 (s, 3H, --NCH₃), 3.67 (s, 3H, --CO₂ CH₃), 3.74 (d, J=17.0 Hz, 1H, --HCHCN), 3.87 (d, J=17.0 Hz, 1H, --HCHCN), 7.7 (m, 2H, Ar-H), 8.2 (d, J=9.1 Hz, 1H, Ar-H); IR (KBr, cm⁻¹): 2250 (CN), 1770 (CO), 1720 (CO), 1675 (CO); MS (m/e): 306 (M⁺), 247 (M⁺ --CO₂ CH₃); M.P. 130°-132° C.

Anal. Calc'd: C, 54.83; H, 3.62; N, 9.13. Found: C, 54.74; H, 3.74; N, 8.89.

Step d) 4-(2-Amino-2-oxoethyl)-2-[(4-bromo-2-fluorophenyl)methyl]-6-fluoro-1,2,3,4-tetrahydro-1,3-dioxo-4-isoquinolinecarboxylic Acid Methyl Ester.

Dry HCl gas was passed through a cold (0° C.) suspension of 2-[(4-bromo-2-fluorophenyl)methyl]-4-cyanomethyl-6-fluoro-1,2,3,4-tetrahydro-1,3-dioxo-4-isoquinolinecarboxylic acid methyl ester (7.7 g, 16.63 mmol) in dimethyl ether (300 mL) and anhydrous MeOH (2.02 mL, 49.89 mmol). The suspension during the introduction of the HCl gas turned into a solution. The mixture was kept at room temperature for 4.5 days and then hexane (500 mL) was added. Most of the volatiles were removed in vacuo to the point that a white solid started to precipitate, and the mixture was cooled to 0° C. for 5 hours. The precipitated solid was filtered, washed with hexane and dried to yield a white solid (7.56 g, 95%). ¹ H NMR (DMSO-d₆, 400 MHz): δ 3.49 (d, J=16.65 Hz, 1H, --CH₂ CONH₂), 3.56 (s, 3H, --CO₂ CH₃), 3.59 (d, J=16.65 Hz, 1H, --CH₂ CONH₂), 5.08 (dd, J=15.48 Hz, 2H, --NCH₂), 6.94 (s, 1H, --CONH₂), 7.21 (t, J=8.22 Hz, 1H, Ar-H), 7.30 (dd, J=8.27 Hz, 1.64 Hz, 1H, Ar-H), 7.38-7.46 (m, 2H, Ar-H), 7.51 (s, 1H, --CONH₂), 7.54 (dd, J=9.81 Hz, 1.83 Hz, 1H, Ar-H), 8.20 (dd, J=8.74 Hz, 5.84 Hz, 1H, Ar-H); IR (KBr, cm⁻¹): 3440 (NH), 3350 (NH), 1740 (CO), 1710 (CO), 1670 (CO), 1660 (CO); MS (m/e): 481 (M+H)⁺ ; M.P. 202°-204° C.

Anal. Calc'd: C, 49.92; H, 3.14; N, 5.82. Found: C, 49.79; H, 3.36; N, 5.51.

The following compounds were obtained in substantially the same manner as that of Example 1, Step d): 4-(2-Amino-2oxoethyl)-2-[(4-bromo-2-fluorophenyl)methyl]-1,2,3,4-tetrahydro-1,3-dioxo-4-isoquinolinecarboxylic Acid Methyl Ester

¹ H NMR (DMSO-d₆, 400 MHz): δ 3.53 (s, 3H, --CO₂ CH₃), 3.51 (q, J=16.6 Hz, 2H, --CH₂ CONH₂), 5.1 (q, J=15.4 Hz, 2H, --NCH₂ --), 6.88 (s, 1H, --CONH₂), 7.23 (t, J=8.0 Hz, 1H, Ar-H), 7.3 (dd, J=8.3 Hz, 1.84 Hz, 1H, Ar-H), 7.46 (d, J=7.98 Hz, 1H, Ar-H), 7.52 (s, 1H, --CONH₂), 7.54-7.60 (m, 2H, Ar-H), 7.75 (dt, J=7.76 Hz, 1.39 Hz, 1H, Ar-H), 8.1 (dd, J=7.87 Hz, 1.22 Hz, 1H, Ar-H); IR (KBr, cm⁻¹): 3450 (NH), 17340 (CO), 1720 (CO), 1670 (CO); MS (m/e): 462 (M⁺); M.P. 180°-182° C.

Anal. Calc'd: C, 51.84; H, 3.46; N, 6.05. Found: C, 51.72; H, 3.65; N, 5.91.

4-(2-Amino-2-oxoethyl)-6-chloro-1,2,3,4-tetrahydro-2-methyl-1,3-dioxo-4-isoquinolinecarboxylic Acid Methyl Ester

¹ H NMR (DMSO-d₆, 200 MHz): δ 3.26 (s, 3H, --NCH₃), 3.51 (q, J=17.5 Hz, 2H, --CH₂ CONH₂), 3.59 (s, 3H, --CO₂ CH₃), 6.85 (s, 1H, --CONH₂), 7.5 (s, 1H, --CONH₂), 7.53 (d, J=2.0 Hz, 1H, Ar-H), 7.62 (dd, J=8.6 Hz, 2.0 Hz, 1H, Ar-H), 8.16 (d, J=8.0 Hz, 1H, Ar-H); IR (KBr, cm⁻¹): 3420 (NH), 1760 (CO), 1710 (CO), 1660 (CO); MS (m/e): 325 (M+H)⁺ ; M.P. 220°-222° C.

Anal. Calc'd: C, 51.78; H, 4.03; N, 8.63. Found: C, 51.76; H, 4.20; N, 8.32.

4-(2-Amino-2-oxoethyl)-1,2,3,4-tetrahydro-2-methyl-1,3-dioxo-4-isoquinolinecarboxylic Acid Methyl Ester

¹ H NMR (DMSO-d₆, 200 MHz): δ 3.27 (s, 3H, --NCH₃), 3.49 (s, 2H, --CH₂ CO₂ H), 3.56 (s, 3H, --CO₂ CH₃), 6.78 (s, 1H, --CONH₂), 7.4-7.6 (m, 3H, Ar-H, --CONH₂), 7.69 (dt, J=7.6 Hz, 2 Hz, 1H, Ar-H), 8.16 (d, J=8.2 Hz, 1H, Ar-H); IR (KBr, cm⁻¹): 3420 (NH), 1760 (CO), 1660 (CO); MS (m/e): 291 (M+H)⁺ ; M.P. 229°-231° C.

Anal. Calc'd: C, 57.93; H, 4.86; N, 9.65. Found: C, 57.59; H, 4.93; N, 9.49.

Step e):

2-[(4-Bromo-2-fluorophenyl)methyl]-6-fluorospiro[isoquinoline-4(1H),3'-pyrrolidine]-1,2',3,5'(2H)-tetrone

To a solution of 4-(2-amino-2-oxoethyl)-2-[(4-bromo-2-fluorophenyl)methyl]-6-fluoro-1,2,3,4-tetrahydro-1,3-dioxo-4-isoquinolinecarboxylic acid methyl ester (6.0 g, 12.47 mmol) in DMF (50 mL) was added portionwise NaH (80% dispersion in oil, 374.2 mg, 12.47 mmol) over a 10 minute period. After stirring for 30 minutes, the mixture was poured into H₂ O, acidified with HCl (2N) and extracted with EtOAc. The organic extracts were dried over MgSO₄. Evaporation and purification by flash chromatography (hexane/EtOAc 3/1) on acid washed silica gel (5% H₃ PO₄ in MeOH), yielded a white solid (4.3 g, 86%). ¹ H NMR (DMSO-d₆, 400 MHz): δ 3.44 (s, 2H, CONH--), 5.05 (s, 2H, --CNH₂ --), 7.14 (t, J=8.42 Hz, 1H, Ar-H), 7.32 (dd, J=7.58 Hz, 1.26 Hz, 1H, Ar-H), 7.48 (dt, J=8.64 Hz, 2.1 Hz, 1H, Ar-H), 7.53 (dd, 9.89 Hz, 1.89 Hz, 1H, Ar-H), 7.75 (dd, 9.69 Hz, 2.32 Hz, 1H, Ar-H), 8.22 (dd, J=8.84 Hz, 5.89 Hz, 1H, Ar-H), 12.0 (s, 1H, --CONHCO--); IR (KBr, cm⁻¹): 3400 (NH), 3260 (NH), 1735 (CO), 1680 (CO); MS (m/e): 449 (M+H)⁺ ; M.P. 230°-232° C.

Anal. Calc'd: C, 50.80; H, 2.47; N, 6.24. Found: C, 50.87; H, 2.53; N, 6.08.

The following compounds were prepared in substantially the same manner as that of example 1 step e):

2-[(4-Bromo-2-fluorophenyl)methyl]spiro[isoquinoline-4(1H),3'-pyrrolidine]-1,2',3,5'(2H)-tetrone

¹ H NMR (DMSO-d₆, 400 MHz): δ 3.47 (J=18.24 Hz, 2H, --CH₂ CONH--), 5.06 (s, 2H, --NCH₂ --), 7.14 (t, J=8.2 Hz, 1H, Ar-H), 7.33 (dd, J=8.28 Hz, 1.71 Hz, 1H, Ar-H), 7.55 (dd, J=9.9 Hz, 1.8 Hz, 1H, Ar-H), 7.62 (t, J=7.6 Hz, 1H, Ar-H), 7.68 (d, J=7.78 Hz, 1H, Ar-H), 7.78 (dt, J=8.85 Hz, 1.12 Hz, 1H, Ar-H), 8.15 (dd, J=7.86 Hz, 1.3 Hz, 1H, Ar-H), 12.01 (s, 1H, --CONHCO--); IR (KBr, cm⁻¹): 3450 (NH), 3250 (NH), 1730 (CO), 1680 (CO); MS (m/e): 430 (M⁺), 387 (M⁺ --CONH); M.P. 112°-114° C.

Anal. Calc'd: C, 52.92; H, 2.80; N, 6.50. Found: C, 52.61; H, 2.70; N, 6.46.

6-Chloro-2-methylspiro[isoquinoline-4(1H)3'-pyrrolidine]-1,2',3,5'(2H)-tetrone

¹ H NMR (DMSO-d₆, 400 MHz): δ 3.22 (s, 3H, --NCH₃), 3.38 (s, 2H, CH₂ CONH--), 7.66 (dd, J=8.55 Hz, 2.02 Hz, 1H), Ar-H), 7.92 (d,J=1.97 Hz, 1H, Ar-H), 8.13 (d, J=8.52 Hz, 1H, Ar-H), 11.99 (s, 1H, --CONHCO--); IR (KBr, cm⁻¹): 3350 (NH), 1750 (CO), 1730 (CO), 1660 (CO); MS (m/e): 293 (M+H)⁺ ; M.P. 213°-214° C.

Anal. Calc'd: C, 53.35; H, 3.10; N, 9.57. Found: C, 53.43; H, 3.09; N, 9.38.

2-Methylspiro[isoquinoline-4(1H),3'-pyrrolidine]-1,2',3,5'(2H)-tetrone

¹ H NMR (DMSO-d₆, 400 MHz): δ 3.24 (s, 3H, --N--CH₃), 3.43 (q, J=18.38 Hz, 2H, --CH₂ CONH--), 7.58-7.64 (m, 2H, Ar-H), 7.74 (dt, J=7.64 Hz, 1.2 Hz, 1H, Ar-H), 8.15 (dd, J=7.72 Hz, 0.94 Hz, 1H, Ar-H), 12.0 (2, 1H, --CONHCO--), IR (KBr, cm⁻¹): 3340 (NH), 1720 (CO), 1660(CO); MS (m/e): 258 (M⁺); M.P. 224°-225° C.

Anal. Calc'd: C, 60.47; H, 3.90; N, 10.85. Found: C, 60.27; H, 4.03; N, 10.82. 

I claim:
 1. The process for the production of compounds of formula I ##STR4## wherein: R¹ is hydrogen, halogen and R² is dihalogen substituted benzyl or methyl which comprises:a) reacting the compound of formula (II) ##STR5## wherein R¹ and R² are as defined above with dimethyl malonate and NaH in the presence of a catalytic amount of CuBr to produce the compound of formula (III) ##STR6## b) reacting the compound of formula (III) wherein R¹ and R² are as defined above with SOCl₂ and subsequently treating with R² NH₂ in the presence of Et₃ N in a conventional solvent to produce the compound of formula (IV) ##STR7## wherein R¹ and R² are as defined above c) reacting said compound of formula (IV) with bromoacetonitrile in the presence of K₂ CO₃ in a conventional solvent to produce the compound of formula (V) ##STR8## wherein R¹ and R² are as defined above d) reacting said compound of formula (V) with anhydrous hydrogen chloride gas in methanol and diethyl ether to produce the compound of formula (VI) ##STR9## wherein R¹ and R² are as defined above and e) reacting said compound of formula (VI) with a base in a conventional solvent to produce the compound of formula (I). 